The bisphosphonic acid or its pharmaceutically acceptable salts are important class of medicaments useful in the treatment of diseases of bone and calcium metabolism. Such diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossificans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions. In particular bisphosphonates, like ethane-1-hydroxy-1,1-diphosphonic acid (EHDF), propane-3-amino-1-hydroxy-1,1-diphosphonic acid (APD), dichloromethane diphosphonic acid, 3-amino-1-hydroxypropylidenediphosphonic acid (PAMIDRONIC ACID), 4-amino-1-hydroxybutylidene-1,1-diphosphonic acid (ALENDRONIC ACID), 1-hydroxy-2-(1-imidazolyl)ethylidine-1,1-diphosphonic acid (ZOLEDRONIC ACID) and 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-diphosphonic acid (RISEDRONIC ACID) have been the subject of considerable research efforts in this area. Paget's disease and heterotropic ossification are currently successfully treated with EHDP and Risedronic acid. The diphosphonates tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss.
Several methods for making bisphosphonic acids or its pharmaceutically acceptable salts have been disclosed. The syntheses are based on reacting a carboxylic acid with a mixture of phosphorous acid and one of the following phosphorus halides: phosphorus trichloride (PCl3), phosphorus oxychloride (POCl3), phosphorus pentachloride (PCl5), phosphorus tribromide (PBr3), phosphorus oxybromide (POBr3) or phosphorus pentabromide (PBr5), then quenching the reaction mixture with water or a non-oxidizing aqueous acid, followed by heating to hydrolyze the phosphorus intermediates to the final product.
U.S. Pat. No. 4,407,761 describes the synthesis of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronic acid) and other bisphosphonic acids. The reaction has been carried out in the presence of diluent, e.g. chlorinated hydrocarbons, especially chlorobenzene, which does not solubilize the reaction components and serves only as a heat carrier. The reaction starts as a two-phase system, in which the melted phase gradually thickens into a non-stirrable mass. This semi solid sticky mass finally turns into a hard, rigid material, thereby coating the walls of the reaction vessel and thus preventing the smooth heat transfer and complicating the product work-up. The overall yield of this process is variable i.e. 45% to 56%. The solvent i.e. chlorobenzene used in the reaction is carcinogenic in nature and thus not recommendable for industrial scale.
U.S. Pat. No. 4,922,007 and U.S. Pat. No. 5,019,651 reveal a solution to the solidification. Methanesulfonic acid (MSA) is used to solubilize the reaction components and keep the reaction mixture stirrable up to completion of the reaction. The optimum temperature of phosphonylation reactions using phosphorus trichloride is 90° C. or high. Although the problems with physical characteristics of the reaction appeared solved, a safety problem surfaced. Methanesulfonic acid reacts with phosphorus trichloride and under adiabatic conditions, i.e. above 85° C., the reaction mixture becomes uncontrollably exothermic, which is accompanied by high pressure and, therefore, is not very safe on large-scale production.
U.S. Pat. No. 5,908,959 employs polyalkylene glycols as reaction solvent for synthesizing bisphosphonates. The use of polyalkylene glycols on industrial scale is not very feasible as they are difficult to recover in pure form for reuse.
U.S. Pat. No. 5,648,491 describes that the phosphonylation reaction is carried out in a continuous stirred tank reactor. According to this invention more favorable surface/volume ratio results in better heat transfer and the smaller volume of the reaction mixture reduces the probability of an unexpected thermal event. The disadvantage of this process is that special and expensive equipment is required. Moreover, this continuous operation results in the formation of different dimers, oligomers and polymers, which are present as impurities in the product.
According to U.S. Pat. No. 6,573,401 the problems mentioned in the prior art are solved by the use of methanesulfonic anhydride as a solvent for producing alendronic acid with the overall yield of the process is 65-77%, but the high cost of the solvent renders the method difficult to apply at an industrial level.
US Patent Application No. 20040043967 A1 describes the preparation of bisphosphonic acids by using the diluents other than halogenated hydrocarbons, but overall yield of the process is 56% to 80%. On the other hand U.S. Pat. No. 6,562,974 describes the preparation of bisphosphonates in an overall yield of 77% by using phosphorous acid as a reactant/solvent in presence of base. The disadvantage of this process is that the reaction mixture becomes very viscous without a solvent.
Thus there remains a need for a safe, economical and efficient industrial process for preparing bisphosphonic acids that is free from above-mentioned drawbacks and achieves high yields in environmental friendly conditions, which can also be further extended for the preparation of new polymorphs.
Apart from above mentioned process patents few polymorphs patents and patent applications are available. For example US Patent Application no. 20050054616 A1 describes the zoledronic acid or its pharmaceutically acceptable salts in crystalline as well as in amorphous form. This patent application also describes the process for their preparation. U.S. Pat. No. 6,410,520 describes the process for the preparation of risedronate sodium polymorphs in heripentahydrate and monohydrate crystalline forms, whereas US Patent Application no. 20030195170 describes different crystalline forms and their process for preparation of risedronate sodium.
The aim of the present invention is to provide a process, which is safe, economical, environmental friendly and feasible at commercial scale as well as high yielding and above all it is free from all above-mentioned disadvantages of prior art. This process is further extended for the preparation of novel forms of bisphosphonic acid.